New highly toxic bile acids derived from deoxycholic acid, chenodeoxycholic acid and lithocholic acid

Bioorganic & Medicinal Chemistry
Ferenc MajerJohn F Gilmer

Abstract

We have prepared a new panel of 23 BA derivatives of DCA, chenodeoxycholic acid (CDCA) and lithocholic acid (LCA) in order to study the effect of dual substitution with 3-azido and 24-amidation, features individually associated with cytotoxicity in our previous work. The effect of the compounds on cell viability of HT-1080 and Caco-2 was studied using the 3-[4,5-dimethylthizol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. Compounds with high potency towards reduction of cell viability were further studied using flow cytometry in order to understand the mechanism of cell death. Several compounds were identified with low micromolar IC₅₀ values for reducing cell viability in the Caco-2 and HT1080 cell lines, making them among the most potent BA apoptotic agents reported to date. There was no evidence of relationship between overall hydrophobicity and cytotoxicity supporting the idea that cell death induction by BAs may be structure-specific. Compounds derived from DCA caused cell death through apoptosis. There was some evidence of selectivity between the two cell lines studied which may be due to differing expression of CD95/FAS. The more toxic compounds increased ROS production in Caco-2 cells, and co-incubation with the ant...Continue Reading

References

Dec 16, 2006·Current Cancer Drug Targets·Nam Deuk KimYung Hyun Choi
May 20, 2008·Cellular and Molecular Life Sciences : CMLS·A F Hofmann, L R Hagey
May 7, 2009·Journal of Lipid Research·Joana D AmaralCecília M P Rodrigues
Jul 27, 2011·Apoptosis : an International Journal on Programmed Cell Death·Juan Ignacio BarrasaM Antonia Lizarbe
Jan 14, 2012·Expert Opinion on Therapeutic Targets·María Villa-Morales, José Fernández-Piqueras
May 3, 2012·Journal of Lipid Research·Geoffrey PorezBart Staels
Jan 1, 2013·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Juan I BarrasaJavier Turnay

❮ Previous
Next ❯

Citations

Jun 16, 2015·Acta Oncologica·Roberta M Manzat-SaplacanOvidiu Balacescu
Jul 28, 2016·European Journal of Medicinal Chemistry·Shi-Wei MaoFan Yang
Sep 10, 2014·Nature Reviews. Microbiology·Petra LouisHarry J Flint
Feb 10, 2017·Journal of Labelled Compounds & Radiopharmaceuticals·Martin A HayesCharles S Elmore
Jun 24, 2017·Current Pharmacology Reports·Nicholas J W RattrayCaroline H Johnson
Dec 31, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Maria Luisa NavacchiaDaniela Perrone
May 4, 2016·Gastroenterology·Robert H Palmer

❮ Previous
Next ❯

Related Concepts

Related Feeds

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis